Drug eluting beads (DEBs) have been recently developed as a new mean of delivering chemotherapeutic agents in a targeted and controllable fashion. DEBs, used in chemoembolization therapies, such as transarterial chemo-embolization (TACE), are embolizing beads that can be loaded with chemotherapeutic agents and that can slowly release them in the tumour vasculature with the advantage of lower systemic toxicity and sustained local activity. Thus TACE combines therapeutic effects of peripheral arterial occlusion with the local administration of chemotherapeutic agents. The ideal TACE scheme should allow maximum and sustained concentration of the chemotherapeutic agent within the tumour with minimal systemic exposure combined with calibrated tumour vessel obstruction.
Recently it has been reported that DEBs have the ability to actively sequester doxorubicin hydrochloride from a solution and release it in a controlled and sustained fashion. They have been shown to substantially diminish the amount of chemotherapeutic agent that reaches the systemic circulation, thus significantly increasing the local concentration of the drug and the antitumoral efficacy. For example alginate beads loaded with doxorubicin have been reported (Yao Xue Xue Bao. 2006 August; 41 (8):778-83), or polyvinyl alcohol hydrogel beads modified with sulphonate groups loaded with doxorubicin have been also reported (Clin Cancer Res. 2006 Apr. 15; 12(8):2563-7), for chemoembolization of the liver and demonstrated a sustained delivery in vivo. Comparison of drug loading and delivery of doxorubicin and irinotecan for different beads has been also recently reported (Jordan et al, J Vasc Int Radiol 21:1084-1090, 2010). These systems use the ion-exchange properties of the polymer of beads to sequester cationically charged drugs such as doxorubicin hydrochloride, and provide a method of controlled and sustained post intraarterial delivery to a specific site within the body, in WO 2004/071495 and WO 2006/027567, beads comprising water-insoluble polymer, having an overall anionic charge and electrostatically associated with the polymer an anthracycline or camptothecin compound are disclosed. The DEBs may be used to embolize tumours, for instance a hepatocellular carcinoma. WO 2008/138758 also discloses beads (microspheres) loaded with nemorubicin hydrochloride.
However, preparing drug-loaded beads is not a straightforward procedure, especially if they should be loaded with chemotherapeutic agents of low solubility in aqueous media. This solubility can be insufficient to reach useful therapeutic dose, such as for sorafenib tosylate. In the case where apparent solubility is sufficient to reach useful therapeutic dose, it may appear that some delayed precipitation occurs; making impossible the utilization of such preparation in a clinic setup. For example, sunitinib base or malate can be dissolved in standard media used for loading anthracycline drugs, such as doxorubicine. However in such standard solutions, sunitinib base or malate precipitate within a short period of time which makes loading sunitinib into beads and obtaining stable solutions in drug-loaded beads very problematic. In addition, no liquid oral or parenteral solution of any sunitinib salt is commercially available, that could be used to load DEBs. Only sunitinib suspensions in acidic media have been proposed in the literature for oral route (Navid F et al, Ann Pharmacotherapy 42:962-966, 2008; Sistla A et al Drug Dev Ind Pharm 30(1):19-25, 2004), but this is not suitable for loading DEBs. WO 2007/090897 further discloses a method for loading beads with water insoluble chemotherapeutic agents by using organic solvents. However, such an approach is not adequate for extemporaneous preparation by the medical staff.
Therefore there remains an unmet need to provide drug-loaded beads with chemotherapeutic agents of low aqueous solubility, such as anti-angiogenic agents, more particularly such as sunitinib.